Ketamine's rapid and sustained antidepressant effects are driven by distinct mechanisms.

Administration of multiple subanesthetic doses of ketamine increases the duration of antidepressant effects relative to a single ketamine dose, but the mechanisms mediating this sustained effect are unclear. Here, we demonstrate that ketamine's rapid and sustained effects on affective behavior are mediated by separate and temporally distinct mechanisms. The rapid effects of a single dose of ketamine result from increased activity of immature neurons in the hippocampal dentate gyrus without an increase in neurogenesis. Treatment with six doses of ketamine over two weeks doubled the duration of behavioral effects after the final ketamine injection. However, unlike ketamine's rapid effects, this more sustained behavioral effect did not correlate with increased immature neuron activity but instead correlated with increased numbers of calretinin-positive and doublecortin-positive immature neurons. This increase in neurogenesis was associated with a decrease in bone morphogenetic protein (BMP) signaling, a known inhibitor of neurogenesis. Injection of a BMP4-expressing lentivirus into the dentate gyrus maintained BMP signaling in the niche and blocked the sustained - but not the rapid - behavioral effects of ketamine, indicating that decreased BMP signaling is necessary for ketamine's sustained effects. Thus, although the rapid effects of ketamine result from increased activity of immature neurons in the dentate gyrus without requiring an increase in neurogenesis, ketamine's sustained effects require a decrease in BMP signaling and increased neurogenesis along with increased neuron activity. Understanding ketamine's dual mechanisms of action should help with the development of new rapid-acting therapies that also have safe, reliable, and sustained effects.

A broad-taxa approach as an important concept in ecotoxicological studies and pollution monitoring.

Aquatic invertebrates play a pivotal role in (eco)toxicological assessments because they offer ethical, cost-effective and repeatable testing options. Additionally, their significance in the food chain and their ability to represent diverse aquatic ecosystems make them valuable subjects for (eco)toxicological studies. To ensure consistency and comparability across studies, international (eco)toxicology guidelines have been used to establish standardised methods and protocols for data collection, analysis and interpretation. However, the current standardised protocols primarily focus on a limited number of aquatic invertebrate species, mainly from Arthropoda, Mollusca and Annelida. These protocols are suitable for basic toxicity screening, effectively assessing the immediate and severe effects of toxic substances on organisms. For more comprehensive and ecologically relevant assessments, particularly those addressing long-term effects and ecosystem-wide impacts, we recommended the use of a broader diversity of species, since the present choice of taxa exacerbates the limited scope of basic ecotoxicological studies. This review provides a comprehensive overview of (eco)toxicological studies, focusing on major aquatic invertebrate taxa and how they are used to assess the impact of chemicals in diverse aquatic environments. The present work supports the use of a broad-taxa approach in basic environmental assessments, as it better represents the natural populations inhabiting various ecosystems. Advances in omics and other biochemical and computational techniques make the broad-taxa approach more feasible, enabling mechanistic studies on non-model organisms. By combining these approaches with in vitro techniques together with the broad-taxa approach, researchers can gain insights into less-explored impacts of pollution, such as changes in population diversity, the development of tolerance and transgenerational inheritance of pollution responses, the impact on organism phenotypic plasticity, biological invasion outcomes, social behaviour changes, metabolome changes, regeneration phenomena, disease susceptibility and tissue pathologies. This review also emphasises the need for harmonised data-reporting standards and minimum annotation checklists to ensure that research results are findable, accessible, interoperable and reusable (FAIR), maximising the use and reusability of data. The ultimate goal is to encourage integrated and holistic problem-focused collaboration between diverse scientific disciplines, international standardisation organisations and decision-making bodies, with a focus on transdisciplinary knowledge co-production for the One-Health approach.

Development and Validation of a 15-gene Expression Signature with Superior Prognostic Ability in Stage II Colorectal Cancer.

Currently, there is no consensus about the use of adjuvant chemotherapy for patients with stage II colorectal cancer. Here, we aimed to identify and validate a prognostic mRNA expression signature for the stratification of patients with stage II colorectal cancer according to their risk for relapse. First, publicly available mRNA expression profiling datasets from 792 primary, stage II colorectal cancers from six different training cohorts were analyzed to identify genes that are consistently associated with patient relapse-free survival (RFS). Second, the identified gene expression signature was experimentally validated using NanoString technology and computationally refined on primary colorectal cancer samples from 205 patients with stage II colorectal cancer. Third, the refined signature was validated in two independent publicly available cohorts of 166 patients with stage II colorectal cancer. Bioinformatics analysis of training cohorts identified a 61-gene signature that was highly significantly associated with RFS (HR = 37.08, P = 2.68*10-106, sensitivity = 89.29%, specificity = 89.61%, and AUC = 0.937). The experimental validation and refinement revealed a 15-gene signature that robustly predicted relapse in three independent cohorts: an in-house cohort (HR = 20.4, P = 8.73*10-23, sensitivity = 90.32%, specificity = 80.99%, AUC = 0.812), GSE161158 (HR = 5.81, P = 3.57*10-4, sensitivity = 64.29%, specificity = 81.67%, AUC = 0.796), and GSE26906 (HR = 7.698, P = 7.26*10-8, sensitivity = 61.54%, specificity = 78.33%, AUC = 0.752). In the pooled training cohort, the 15-gene signature (HR = 4.72, P = 7.76*10-25, sensitivity = 75%, specificity = 67.44%, AUC = 0.784) was superior to the Oncotype DX colon 7-gene signature (HR = 2.698, P = 6.3*10-8, sensitivity = 62.16%, specificity = 55.5%, AUC = 0.633). We report the identification and validation of a novel mRNA expression signature for robust prognostication and stratification of patients with stage II colorectal cancer, with superior performance in the analyzed validation cohorts when compared with clinicopathologic biomarkers and signatures currently used for stage II colorectal cancer prognostication. Significance: We identified and validated a 15-gene expression signature for robust prognostication and stratification of patients with stage II colorectal cancer, with superior performance when compared with currently used biomarkers. Therefore, the 15-gene expression signature has the potential to improve the prognostication and treatment decisions for patients with stage II colorectal cancer.

Could Acute Myeloid Leukemia Have Presented Even Worse? "Uncommon Cause of Concurrently Multivessel Thrombosis". / A Leucemia Mieloide Aguda Poderia ter se Apresentado Ainda Pior? "Causa Incomum de Trombose Multiarterial Concomitante".

Acute promyelocytic leukemia (APL) is a subgroup of acute myeloid leukemia (AML). Although it is known that hemorrhagic complications are common, thrombotic complications are not as rare as thought. However, myocardial infarction and ischemic stroke incidence are very rare during AML. Here, we present the astonishing case of APL diagnosed with pancytopenia in its presentation with acute myocardial infarction and ischemic stroke.

A leucemia promielocítica aguda (LPA) é um subgrupo da leucemia mieloide aguda (LMA). Embora se saiba que as complicações hemorrágicas são comuns, as complicações trombóticas não são tão raras quanto se pensa. No entanto, infarto do miocárdio e incidência de acidente vascular cerebral isquêmico são muito raros durante a LMA. Aqui, apresentamos o caso surpreendente de LPA diagnosticada com pancitopenia em sua apresentação com infarto agudo do miocárdio e acidente vascular cerebral isquêmico.

Why Some Mice Are Smarter than Others: The Impact of Bone Morphogenetic Protein Signaling on Cognition.

Inbred mice (C57Bl/6) display wide variability in performance on hippocampal-dependent cognitive tasks. Examination of microdissected dentate gyrus (DG) after cognitive testing showed a highly significant negative correlation between levels of bone morphogenetic protein (BMP) signaling and recognition memory. Cognitive performance decline during the aging process, and the degree of cognitive decline is strongly correlated with aging-related increases in BMP signaling. Further, cognitive performance was impaired when the BMP inhibitor, noggin, was knocked down in the DG. Infusion of noggin into the lateral ventricles enhanced DG-dependent cognition while BMP4 infusion led to significant impairments. Embryonic overexpression of noggin resulted in lifelong enhancement of recognition and spatial memory while overexpression of BMP4 resulted in lifelong impairment, substantiating the importance of differences in BMP signaling in wild-type mice. These findings indicate that performance in DG-dependent cognitive tasks is largely determined by differences in levels BMP signaling in the dentate gyrus.

Nasal Airway Function After Prophylactic Intranasal Surgery for Excessive Maxillary Superior Repositioning: A Retrospective Cohort Study Using the Nasal Obstruction Symptom Evaluation Scale.

PURPOSE: The purpose of this study is to evaluate the degree of nasal airway function after simultaneous intranasal corrective surgery and bimaxillary surgery in patients with excessive superior maxillary repositioning. MATERIALS AND METHODS: A retrospective cohort study was conducted on consecutive LeFort I superior repositioning patients who also underwent simultaneous intranasal surgery to prevent airway obstruction between 2015 and 2019. The Nasal Obstruction Symptom Evaluation (NOSE) scale was administered to all participants before the operation and after 1 year. RESULTS: Fifteen patients (n=12 females; n=3 males) among 440 bimaxillary orthognathic surgery patients were enrolled with inclusion criteria of maxillary impaction between 8 and 12 mm. All subjects underwent at least LeFort I osteotomy, septoplasty, bilateral inferior turbinectomy, and bilateral sagittal split osteotomy. Two patients received custom-made total joint prosthesis. The primary outcome variable investigated was nasal function. The mean preop Nasal Obstruction Symptom Evaluation score was 24.33 and the mean postop score was 5. CONCLUSIONS: Intranasal procedures performed simultaneously with 8 mm or more maxillary impaction improves postoperative functional outcome in terms of nasal airway patency and breathing. Partial inferior turbinectomies and septoplasty should be performed consistently to avoid nasal obstruction if the impaction of upper jaw exceeds 8 mm.

A Leucemia Mieloide Aguda Poderia ter se Apresentado Ainda Pior? "Causa Incomum de Trombose Multiarterial Concomitante" / Could Acute Myeloid Leukemia Have Presented Even Worse? "Uncommon Cause of Concurrently Multivessel Thrombosis"

Resumo A leucemia promielocítica aguda (LPA) é um subgrupo da leucemia mieloide aguda (LMA). Embora se saiba que as complicações hemorrágicas são comuns, as complicações trombóticas não são tão raras quanto se pensa. No entanto, infarto do miocárdio e incidência de acidente vascular cerebral isquêmico são muito raros durante a LMA. Aqui, apresentamos o caso surpreendente de LPA diagnosticada com pancitopenia em sua apresentação com infarto agudo do miocárdio e acidente vascular cerebral isquêmico.

Abstract Acute promyelocytic leukemia (APL) is a subgroup of acute myeloid leukemia (AML). Although it is known that hemorrhagic complications are common, thrombotic complications are not as rare as thought. However, myocardial infarction and ischemic stroke incidence are very rare during AML. Here, we present the astonishing case of APL diagnosed with pancytopenia in its presentation with acute myocardial infarction and ischemic stroke.

Metal-organic frameworks as photocatalysts in energetic and environmental applications.

Metal-organic frameworks (MOFs) are an exciting new class of porous materials with great potential for photocatalytic applications in the environmental and energy sectors. MOFs provide significant advantages over more traditional materials when used as photocatalysts due to their high surface area, adaptable topologies, and functional ability. In this article, we summarize current developments in the use of MOFs as photocatalysts for a variety of applications, such as CO2 reduction, water splitting, pollutant degradation, and hydrogen production. We discuss the fundamental properties of MOFs that make them ideal for photocatalytic applications, as well as strategies for improving their performance. The opportunities and challenges presented by this rapidly expanding field are also highlighted.

Acoustic Biotopes, Listeners and Sound-Induced Action: A Case Study of Operating Rooms.

As socio-technological environments shape and direct listener behaviour, an ecological account is needed that encompasses listening in complexity (i.e., multiple listeners, multiple sounds and their sources, and multiple sound-induced actions that ensure the success of a mission). In this study, we explored sound-induced action under the framework of "acoustic biotopes" (a notion of ecological acoustics by Smolders, Aertsen, and Johanessma, 1979 and 1982) in a specific socio-technological environment, i.e., the context of an orthopaedic operating room. Our approach is based on literature research into the topics of environmental psychology and auditory perception and action and in situ observations in healthcare with field recordings, participatory observations, and interviews on the spot. The results suggest a human-centered definition of sound-induced action in acoustic biotopes: Acoustic biotope is an active and shared sound environment with entangled interactions and sound-induced actions taking place in a specific space that has a critical function. Listening in highly functional environments is an individual experience and is influenced by hearing function, physical position and role in an environment, and the task at hand. There is a range of active and passive sound listeners as a function of their attentive state and listeners as sound sources within the acoustic biotope. There are many different sound sources and sound locals in socio-technological environments and sounds have great potential to serve critical information to operators. Overall, our study provides a holistic, multi-layered and yet a listener-centric view on the organisation of complex spaces and the results can immediately be applicable for rethinking the acoustic environment for ORs for better listening and sound-induced action.

Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice.

Ketamine treatment decreases depressive symptoms within hours, but the mechanisms mediating these rapid antidepressant effects are unclear. Here, we demonstrate that activity of adult-born immature granule neurons (ABINs) in the mouse hippocampal dentate gyrus is both necessary and sufficient for the rapid antidepressant effects of ketamine. Ketamine treatment activates ABINs in parallel with its behavioral effects in both stressed and unstressed mice. Chemogenetic inhibition of ABIN activity blocks the antidepressant effects of ketamine, indicating that this activity is necessary for the behavioral effects. Conversely, chemogenetic activation of ABINs without any change in neuron numbers mimics both the cellular and the behavioral effects of ketamine, indicating that increased activity of ABINs is sufficient for rapid antidepressant effects. These findings thus identify a specific cell population that mediates the antidepressant actions of ketamine, indicating that ABINs can potentially be targeted to limit ketamine's side effects while preserving its therapeutic efficacy.

Hippocampal BMP signaling as a common pathway for antidepressant action.

The benefits of current treatments for depression are limited by low response rates, delayed therapeutic effects, and multiple side effects. Antidepressants affect a variety of neurotransmitter systems in different areas of the brain, and the mechanisms underlying their convergent effects on behavior have been unclear. Here we identify hippocampal bone morphogenetic protein (BMP) signaling as a common downstream pathway that mediates the behavioral effects of five different antidepressant classes (fluoxetine, bupropion, duloxetine, vilazodone, trazodone) and of electroconvulsive therapy. All of these therapies decrease BMP signaling and enhance neurogenesis in the hippocampus. Preventing the decrease in BMP signaling blocks the effect of antidepressant treatment on behavioral phenotypes. Further, inhibition of BMP signaling in hippocampal newborn neurons is sufficient to produce an antidepressant effect, while chemogenetic silencing of newborn neurons prevents the antidepressant effect. Thus, inhibition of hippocampal BMP signaling is both necessary and sufficient to mediate the effects of multiple classes of antidepressants.

Activating newborn neurons suppresses depression and anxiety-like behaviors.

The etiology of major depressive disorder (MDD), the leading cause of worldwide disability, is unknown. The neurogenic hypothesis proposes that MDD is linked to impairments of adult neurogenesis in the hippocampal dentate gyrus (DG), while the effects of antidepressants are mediated by increased neurogenesis. However, alterations in neurogenesis and endophenotypes are not always causally linked, and the relationship between increased neurogenesis and altered behavior is controversial. To address causality, we used chemogenetics in transgenic mice to selectively manipulate activity of newborn DG neurons. Suppressing excitability of newborn neurons without altering neurogenesis abolish the antidepressant effects of fluoxetine. Remarkably, activating these neurons is sufficient to alleviate depression-like behavior and reverse the adverse effects of unpredictable chronic mild stress. Our results demonstrate a direct causal relationship between newborn neuronal activity and affective behavior. Thus, strategies that target not only neurogenesis but also activity of newborn neurons may lead to more effective antidepressants.

Evaluation of Endothelial Dysfunction in Bipolar Affective Disorders: Serum Endocan and Urotensin-II Levels.

OBJECTIVE: This study investigated changes in urotensin-II (U-II) and endocan levels which can be used as an early biological marker of endothelial injury in the episode and remission phases of bipolar affective disorder (BAD). METHODS: We compared endocan and U-II levels, which has been shown to be closely associated with neurotransmitter systems in addition to continuity of endothelial structure and inflammatory response, in patients with BAD in remission for at least one year (n=42) and in patients still in manic or depressive episodes (n=16) with healthy controls (n=30). RESULTS: Both endocan and U-II levels were significantly higher in the bipolar patients than in the controls. Endocan and U-II levels were also significantly correlated with one another (p =0.000, r=0.833). Both endocan (p =0.000) and U-II levels (p =0.000) were significantly higher in the bipolar attack group compared to the subjects in remission, and in the remission group compared to the controls. CONCLUSION: In this study we determined significantly higher endocan and U-II levels in BAD compared to the controls, while serum endocan and U-II levels of patients undergoing attacks were also significantly higher than those of the controls and also those of patients in remission.

Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression.

Aging and major depressive disorder are risk factors for dementia, including Alzheimer's Disease (AD), but the mechanism(s) linking depression and dementia are not known. Both AD and depression show greater prevalence in women. We began to investigate this connection using females of the genetic model of depression, the inbred Wistar Kyoto More Immobile (WMI) rat. These rats consistently display depression-like behavior compared to the genetically close control, the Wistar Kyoto Less Immobile (WLI) strain. Hippocampus-dependent contextual fear memory did not differ between young WLI and WMI females, but, by middle-age, female WMIs showed memory deficits compared to same age WLIs. This deficit, measured as duration of freezing in the fear provoking-context was not related to activity differences between the strains prior to fear conditioning. Hippocampal expression of AD-related genes, such as amyloid precursor protein, amyloid beta 42, beta secretase, synucleins, total and dephosphorylated tau, and synaptophysin, did not differ between WLIs and WMIs in either age group. However, hippocampal transcript levels of catalase (Cat) and hippocampal and frontal cortex expression of insulin-like growth factor 2 (Igf2) and Igf2 receptor (Igf2r) paralleled fear memory differences between middle-aged WLIs and WMIs. This data suggests that chronic depression-like behavior that is present in this genetic model is a risk factor for early spatial memory decline in females. The molecular mechanisms of this early memory decline likely involve the interaction of aging processes with the genetic components responsible for the depression-like behavior in this model.

Imidazole/benzimidazole-modified cyclotriphosphazenes as highly selective fluorescent probes for Cu2+: synthesis, configurational isomers, and crystal structures.

Configurational isomers (cis and trans) of imidazole- or benzimidazole-modified cyclotriphosphazenes (3a, 4a or 3b, 4b) were designed, synthesized and investigated as fluorescent probes for metal ions. The newly synthesized compounds were characterized by 1H and 31P NMR, and MALDI MS spectrometry. The configurations of geometric isomers were analyzed by X-ray crystallography and 31P NMR spectroscopy on addition of CSA. The photophysical behaviour and metal ion selectivity of the compounds were investigated by UV/vis and fluorescence spectroscopy. Among the examined 20 metal ions, the fluorescence emissions of the isomer mixtures were quenched by Cu2+ together with Fe2+, Fe3+, Zn2+ and Ni2+ ions, but each individual isomer (3a,b and 4a,b) exhibited an on-off-type fluorescence response with high selectivity towards only Cu2+ with a low limit of detection ranging from 1.27 µM to 2.04 µM. The complex stoichiometries of 3a,b and 4a,b with Cu2+ were determined as 1 : 1 (L/M) using the method of continuous variation (Job's plot) and density functional theory (DFT) calculations; moreover the complex formation of 4a with Cu2+ was unambiguously determined by X-ray crystallographic analysis that is consistent with the results obtained by the Job's plots as well as DFT.

Effects of Ankaferd BloodStopper on dermal healing in diabetic rats.

BACKGROUND/AIM: Diabetes mellitus inhibits wound-induced angiogenesis, impairs the wound healing process, and leads to the development of chronic wounds. Ankaferd BloodStopper (ABS) is a new and promising local haemostatic agent. Although the mechanism of ABS-mediated haemostasis is well established, little is known about the associated histological and biochemical tissue reactions. The aim of this study was to evaluate the effects of this new-generation local haemostatic agent on short-term soft-tissue healing in streptozotocin (STZ)-treated rats. MATERIALS AND METHODS: The 24 Wistar albino rats used in this study were divided into STZ-treated (STZ, n = 12) and nontreated groups (control, n = 12). Four days prior to surgery, rats in the STZ group were subcutaneously administered 60 mg/kg STZ intraperitoneally, while rats in the control group were administered 1 mL saline/kg. An incision was made in the dorsal dermal tissue of all rats, and either ABS or no haemostatic agent (NHAA) was applied to the wound before suturing. All of the rats were euthanised on postoperative day 4. Blood and skin samples were evaluated biochemically and histologically. RESULTS: The results showed that STZ treatment impaired soft-tissue healing, assessed by measuring glutathione and lipid peroxidation levels. Moreover, while good histological results were obtained in the control group treated with ABS, there were fewer benefits in the STZ-treated group. CONCLUSION: ABS's benefits in the control group seemed to lose their effectiveness under STZ medication.

Modeling Fetal Alcohol Spectrum Disorder: Validating an Ex Vivo Primary Hippocampal Cell Culture System.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is the leading nongenetic cause of mental retardation. There are no treatments for FASD to date. Preclinical in vivo and in vitro studies could help in identifying novel drug targets as for other diseases. Here, we describe an ex vivo model that combines the physiological advantages of prenatal ethanol (EtOH) exposure in vivo with the uniformity of primary fetal hippocampal culture to characterize the effects of prenatal EtOH. The insulin signaling pathways are known to be involved in hippocampal functions. Therefore, we compared the expression of insulin signaling pathway genes between fetal hippocampi (in vivo) and primary hippocampal culture (ex vivo). The similarity of prenatal EtOH effects in these 2 paradigms would deem the ex vivo culture acceptable to screen possible treatments for FASD. METHODS: Pregnant Sprague-Dawley rats received 1 of 3 diets: ad libitum standard laboratory chow (control-C), isocaloric pair-fed (nutritional control), and EtOH containing liquid diets from gestational day (GD) 8. Fetal male and female hippocampi were collected either on GD21 (in vivo) or on GD18 for primary culture (ex vivo). Transcript levels of Igf2, Igf2r, Insr, Grb10, Rasgrf1, and Zac1 were measured by reverse transcription quantitative polymerase chain reaction. RESULTS: Hippocampal transcript levels differed by prenatal treatment in both males and females with sex differences observed in the expression of Igf2 and Insr. The effect of prenatal EtOH on the hippocampal expression of the insulin pathway genes was parallel in the in vivo and the ex vivo conditions. CONCLUSIONS: The similarity of gene expression changes in response to prenatal EtOH between the in vivo and the ex vivo conditions ascertains that these effects are already set in the fetal hippocampus at GD18. This strengthens the feasibility of the ex vivo primary hippocampal culture as a tool to test and screen candidate drug targets for FASD.

Thyroxine administration prevents matrilineal intergenerational consequences of in utero ethanol exposure in rats.

The neurodevelopmental fetal alcohol spectrum disorder (FASD) is characterized by cognitive and behavioral deficits in the offspring. Conferring the deficits to the next generation would increase overall FASD disease burden and prevention of this transmission could be highly significant. Prior studies showed the reversal of these behavioral deficits by low dose thyroxine (T4) supplementation to the ethanol-consuming mothers. Here we aim to identify whether prenatal ethanol (PE) exposure impairs hippocampus-dependent learning and memory in the second-generation (F2) progeny, and whether T4 administration to the ethanol-consuming dam can prevent it. Sprague-Dawley (S) dams received control diets (ad libitum and nutritional control) or ethanol containing liquid diet with and without simultaneous T4 (0.3mg/L diet) administration. Their offspring (SS F1) were mated with naive Brown Norway (B) males and females generating the SB F2 and BS F2 progeny. Hippocampus-dependent contextual fear memory and hippocampal expression of the thyroid hormone-regulated type 3 deiodinase, (Dio3) and neurogranin (Nrgn) were assessed. SS F1 PE-exposed females and their SB F2 progeny exhibited fear memory deficits. T4 administration to the mothers of F1 females reversed these deficits. Although SS F1 PE-exposed males also experienced fear memory deficit, this was neither transmitted to their BS F2 offspring nor reversed by prenatal T4 treatment. Hippocampal Dio3 and Nrgn expression showed similar pattern of changes. Grandmaternal ethanol consumption during pregnancy affects fear memory of the matrilineal second-generation progeny. Low dose T4 supplementation prevents this process likely via altering allele-specific and total expression of Dio3 in the hippocampus.